The present invention relates to the field of vascular grafts typically used to replace, line or otherwise repair living blood vessels or other body conduits.
The first effective vascular surgery reported in the literature was the work of T. Gluck who described in 1898 his placement of a vein graft in the carotid artery of a patient in 1894. Carrel and Guthrie reported in 1908 that they had successfully grafted a segment of a dog""s vena cava, previously preserved in formalin, into a carotid artery. Guthrie prophetically concluded that these graft segments did not maintain the viability of living tissue but simply served as a conduit for blood and provided a possible scaffold for the ingrowth of cells. Carrel subsequently and unsuccessfully attempted to use tubes of glass and metal as vascular grafts.
Following the discovery by Voorhees that a loose silk thread lying within the right ventricle of a dog""s heart became coated with an endothelial-like substance, it was proposed that a vascular substitute might be made of such threads. Vorhees et al. described in 1952 the use of short lengths of tubes made from Vinyon xe2x80x9cNxe2x80x9d cloth as replacements for aortic segments in dogs. In 1954, Voorhees and Blakemore described the replacement of 17 abdominal aneurysms and a popliteal aneurysm with synthetic tubes. Years of additional work by vascular surgeons building on this beginning led to the understanding that while conventional synthetic grafts of materials such as polyethylene terephthalate (PET) worked well in large diameter applications (for example, those involving repair of aortic aneurysms), their patency decreased with decreasing diameters. Darling and Linton in 1972 reported that eight-year PET implants in the leg had patency rates of about 10% in comparison to reversed saphenous vein patency rates of about 65-70%.
R. W. Gore invented porous expanded polytetrafluoroethylene (ePTFE) in 1969. He taught in U.S. Pat. Nos. 3,953,566 and 4,187,390 that polytetrafluoroethylene (PTFE) paste extrudate, following removal of the extrusion lubricant, could be rapidly stretched at a temperature below the crystalline melt point of PTFE to create the resulting porous microstructure of nodes interconnected by fibrils. During 1972, Soyer et al. reported using ePTFE tubes as venous replacements in pigs. Matsumoto et al. in 1973 described the use of ePTFE tubes as femoral artery replacements in dogs. In 1976, Campbell et al. first reported the use of ePTFE as a vascular substitute in humans. With further development to ensure adequate mechanical strength, these grafts soon became the standard for small diameter synthetic grafts. Even so, it was recognized that these improved synthetics sometimes did not perform equally as well as autologous saphenous vein grafts. It was noted that synthetic grafts, both PET and ePTFE, generally did not endothelialize beyond 1 or 2 cm from each anastomosis. The primary focus of further work on improved synthetic grafts since then has involved attempts to improve endothelialization of graft luminal surfaces. With regard to ePTFE grafts, this work frequently entailed methods of modifying the surface energy of the graft luminal surfaces to render the hydrophobic PTFE material much more hydrophilic. Conversely, woven PET grafts have been provided with luminal surface coatings of plasma-applied tetrafluoroethylene (TFE) monomer gas as taught by U.S. Pat. No. 4,718,907 to Karwoski et al.
Porosity has long been recognized to be a fundamental characteristic which affects the patency of synthetic vascular grafts; see, for example, the pioneering paper by Wesolowski et al., entitled xe2x80x9cPorosity: primary determinant of ultimate fate of synthetic vascular graftsxe2x80x9d (Suraerv, Vol. 50, No. 1 (July, 1961)). Accordingly, a great deal of the research into ePTFE grafts focused on efforts to optimize the mean fibril length of such grafts. While it has generally been concluded that these grafts were required to have a mean fibril length of at least 5-6 microns and no more than about 90 microns, the data reported in the literature remain inconsistent. See, e.g., Golden et al., xe2x80x9cHealing of polytetrafluoroethylene arterial grafts is influenced by graft porosity,xe2x80x9d J. Vasc. Surg., pp. 838-845 (June, 1990); also, Branson et al., xe2x80x9cExpanded Polytetrafluoroethylene as a Microvascular Graft: A Study of Four Fibril Lengths,xe2x80x9d Plastic and Reconstructive Surgery, Vol. 76, No. 5, pp. 754-763 (November 1985). Commercially available ePTFE grafts typically have a mean fibril length at the luminal surface in the range of about 15-30 microns.
Various ePTFE tubes are described in the patent literature which have different mean fibril lengths on the luminal surface than elsewhere on the tube or which otherwise have at least two differing microstructures within the structure of the tube. They may differ in mean fibril length, directional orientation of the fibrils, or both.
U.S. Pat. Nos. 4,082,893 and 4,208,745 to Okita and 4,332,035 to Mano describe ePTFE tubes, intended for use as vascular grafts, which have been exposed to heat above the crystalline melt temperature of PTFE at their outer surface for a period of time adequate to cause modification of the exterior surface with the result that the microstructure at the exterior surface of the tube becomes coarser as a result of coalescing together of the components of the microstructure, and oriented radially rather than longitudinally. U.S. Pat. No. 4,822,361 to Okita et al. describes that this same type of tube may be optionally impregnated with various resorbable materials including collagen, albumin, chitosan and heparin.
U.S. Pat. No. 4,225,547 to Okita and U.S. Pat. No. 4,743,480 to Campbell et al. describe different methods of orienting the microstructure of ePTFE tubes in different directions at the inner and outer surfaces of the tubes. The tubes are also intended to be used as vascular grafts.
U.S. Pat. No. 4,550,447 to Seiler et al. teaches modification of tubular PTFE extrudate by scoring through a portion of the exterior wall prior to removal of the extrusion lubricant and stretching below the melt temperature, with the result being the creation of a denser, exterior ribbed structure integrally formed with the remainder of the tube. The tube is described as an exteriorly reinforced vascular graft.
Various patents teach coextrusion methods whereby different microstructures may be created in different, concentrically-arranged parts of the wall of ePTFE tubes. Different PTFE or other fluoropolymer resins may be concentrically coextruded to result in the differing microstructures. Likewise other materials such as siloxanes may be included in one or more of the coextruded layers. These patents include U.S. Pat. No. 4,816,339 to Tu et al., U.S. Pat. No. 4,973,609 to Browne, U.S. Pat. No. 5,064,593 to Tamaru et al., and U.S. Pat. No. 5,453,235 to Calcote et al. All of these teach the construction of ePTFE vascular grafts.
Still other patents teach the construction of ePTFE tubes having changing or alternating regions of different porosity along the length of the tube made by making radially oriented segments which differ in porosity between adjacent segments. U.S. Pat. No. 5,433,909 to Martakos et al. teaches a tubular ePTFE vascular graft made having narrow, alternating ring-shaped segments of porous ePTFE and non-porous PTFE. U.S. Pat. No. 5,747128 to Campbell et al. describes an ePTFE vascular graft having alternating ring-shaped segments of more and less dense ePTFE. This graft may be made to be circumferentially distensible to larger diameters, in which form it is useful as an intraluminal graft.
Various patents describe the modification of the luminal surfaces of ePTFE vascular grafts. For example, U.S. Pat. No. 5,246,451 to Trescony et al. teaches modification of ePTFE vascular graft luminal surfaces by gas plasma deposition of fluoropolymer coatings followed by binding of a protein to the modified luminal surface. Optionally, the resulting luminal surface is seeded with endothelial cells. European Patent EP 0 790 042 describes an ePTFE vascular graft wherein the luminal surface is modified to become hydrophilic followed by the immobilization of a tissue-inducting substance onto the surface.
With regard to ePTFE vascular grafts of relatively small mean fibril length, U.S. Pat. No. 4,177,334 to Okita teaches a method of making such a tube which also has a relatively high porosity.
Other patents teach the manufacture of different types of tubular ePTFE forms intended for applications other than vascular grafts. U.S. Pat. No. 4,279,245 to Takagi et al., U.S. Pat. No. 5,529,820 to Nomi et al. and U.S. Pat. No. 5,789,047 to Sasaki et al. describe various ePTFE tubes for use as endoscope tubes wherein at least the luminal surface of the ePTFE tube is made non-porous by filling or coating with siloxanes or fluoropolymers. Tubes of the type taught by Sasaki et al. having a luminal surface of PTFE are relatively smooth but are of very limited porosity, having a bulk density of about 1.55 g/cc (non-porous PTFE having a density of about 2.2 g/cc).
WO/90/06150 teaches the manufacture of a catheter tube wherein a length of non-porous PTFE tubing is provided with an integrally attached, porous ePTFE tip portion. U.S. Pat. No. 4,280,500 to Ono teaches the construction of a catheter introducer device having alternating, ring-shaped sections of non-porous PTFE and porous ePTFE.
The medical literature with respect to PTFE vascular grafts has generally focused on attempts to improve endothelial cell adherence to the luminal graft surfaces. From the voluminous vascular literature, occasional articles have discussed the need for less adherent surfaces. In particular, an article by Lumsden et al., xe2x80x9cNon-porous silicone polymer coating of expanded polytetrafluoroethylene grafts reduces graft neointimal hyperplasia in dog and baboon models,xe2x80x9d J. Vasc. Surg., Vol. 24,No. 5, pp. 825-33 (November 1996), describes the use of silicone to fully or partially coat the luminal surfaces of ePTFE vascular grafts thereby rendering the coated surface non-porous, after which the entire luminal surface of each graft was provided with a gas plasma coating of HFE/H2 monomer gas. In comparison to conventional ePTFE grafts utilized as femoral AV shunts in dogs, the coated grafts were found, following retrieval after 30 days, to have a lesser neointimal area at the venous anastomosis. The grafts used were of 6 mm inside diameter and about 2.5 cm length (i.e., a relatively large diameter graft in comparison to its quite short length, used in a high-flow application). The surface smoothness of the graft was limited by the surface morphology of the luminal surface of the ePTFE graft to which the silicone coating was applied. All grafts remained patent at the conclusion of both the dog and baboon studies. Related work is described in U.S. Pat. No. 4,687,482 to Hanson.
Other non-adherent coatings for use on the luminal surfaces of ePTFE grafts are described. Haimovich et al. describe that the use of chitosan and polyvinyl alcohol coatings may reduce platelet adhesion (xe2x80x9cA New Method for Membrane Construction on ePTFE Vascular Grafts: Effect on Surface Morphology and Platelet Adhesion,xe2x80x9d J. APPl. Polym. Sci., Vol. 63, pp.1393-1400, (1997)).
There remains a need for a small diameter vascular graft which offers improved patency in comparison to conventional available grafts. These grafts may be of particular value in small diameter applications, such as below-knee and coronary applications.
The present invention comprises an implantable device, preferably a vascular graft, having a unique blood contact surface that reduces or prevents the accumulation of occlusive blood components. This is achieved by providing an extremely smooth and substantially non-adherent luminal surface comprised of PTFE and most preferably porous expanded PTFE. The smooth luminal surface is provided in combination with a vascular graft which offers good handling and suture properties. The parameter of concern for smoothness of the luminal surface (surface values) of the present invention is Rq, which is the Root-Mean-Square roughness, defined as the geometric average of the roughness profile from the mean line measured in the sampling length, expressed in units of microns RMS. The luminal surface (i.e., the blood contacting surface) of the vascular graft of the present invention has a surface at least as smooth as about 1.80 microns RMS and more preferably as smooth as about 1.70 microns RMS, 1.60 microns RMS, 1.50 microns RMS, 1.40 microns RMS, 1.30 microns RMS, 1.20 microns RMS, 1.10 microns RMS, 1.00 microns RMS, 0.90 microns RMS, 0.80 microns RMS, 0.70 microns RMS, 0.60 microns RMS, 0.50 microns RMS, 0.40 microns RMS, 0.30 microns RMS and 0.25 RMS. Generally, greater smoothness is more preferred with values of about 1.00 microns RMS or smoother being seen as most preferred. A surface value of about 1.2 microns RMS or less appears to be particularly effective, with 0.6 microns RMS even more effective.
The smooth luminal PTFE surface is preferably the result of providing a smooth surface of small mean fibril length ePTFE material, in comparison to previously available PTFE grafts. The surface smoothness is believed to avoid or reduce adherence of occlusive blood components including blood platelets which are typically of about 2-4 micron diameter. The small pore size (generally characterized as the mean fibril length of the ePTFE microstructure) is preferably less than about 5 microns and more preferably less than about 3 microns. It is believed that the fibril length or pore size may be reduced until the smooth surface is non-porous, substantially non-porous or even entirely non-porous.
Reducing the pore size will in many cases result in reduced invasion of the pores of the graft by cells, and reduced diffusion rate of molecules through the graft wall according to Fick""s Law. An entirely non-porous material would be completely resistant to passage to cells and molecules. The reduced penetration of cells and diffusion of molecules may have additional benefits in improving the function of vascular grafts.
This luminal surface lining is intended to provide a smooth surface to the vascular graft which is believed to be substantially non-adherent to occlusive blood components such as platelets, fibrin and thrombin, and impermeable to cells from the blood, thereby avoiding the formation of an occlusive coating which might ultimately increase in thickness over time and eventually result in graft occlusion. These increasingly thick coatings are known to be particularly problematic at the distal anastomoses of vascular grafts wherein it has been frequently documented that intimal hyperplasia occurring at that location will lead to occlusion and loss of graft patency. While these occlusive blood components are substantially prevented from sticking to the surface of the inventive graft, it is believed that various other blood components such as, for example, various proteins and/or endothelial cells, may still adhere to the surface without leading to a coating of the occlusive blood components responsible for a thickening neointima over time.
The smooth PTFE luminal surface of the graft of the present invention is also anticipated to benefit implant applications which do not involve blood contact. For example, the smooth PTFE luminal surfaces may augment implant performance by reducing bacterial adhesion for grafts used in applications such as biliary grafts and biliary stent grafts. The smooth surface may also offer benefit for applications in which it is considered desirable to avoid tissue fibrosis, such as intra-abdominal adhesion barriers.
While other grafts have been described heretofore having smooth surfaces, none offer such a surface combined with the benefits of a PTFE material. The use of PTFE provides the benefits of many years of experience with this highly biocompatible and extremely chemically inert material while avoiding the use of other materials which are likely to be less biocompatible.
The luminal surface of a graft of the present invention having a smooth, PTFE luminal surface may be demonstrated to provide PTFE at that luminal surface by various methods. XPS (x-ray photoelectron spectroscopy) is the preferred analytical method to identify the presence of PTFE at the luminal surface.
A xe2x80x9cvascular graftxe2x80x9d is herein defined as any conduit or portion thereof intended as a prosthetic device for conveying blood and therefore having a blood contacting (i.e., xe2x80x9cluminalxe2x80x9d) surface. While it is intended primarily as a tubular form, the graft may also be a sheet material useful for patching portions of the circumference of living blood vessels (these materials are generally referred to as cardiovascular patches). Likewise, the term vascular graft includes intraluminal grafts for use within living blood vessels. The inventive grafts as such may also be used as a stent covering on the exterior, luminal or both surfaces of an implantable vascular stent. While it is not required that the smooth luminal surface graft of the present invention be bonded to a stent component, such a bond is preferred. Suitable methods of affixing the graft to a stent as a stent covering are described in U.S. Pat. No. 5,735,892 to Myers et al.
xe2x80x9cConfigured as a vascular graftxe2x80x9d means that the completed device is suitable for use as a vascular graft, i.e., in addition to the smooth luminal surface, that the device is biocompatible, properly proportioned as to appropriate dimensions such as diameter, length and wall thickness, readily attachable to the intended living tissue such as by sutures, offers appropriate handling characteristics such as good flexibility, bending and resistance to kinking during bending, and is sterilizable. Accordingly, vascular grafts are tested for the intended use and labeled as such on packaging and in instructions for use.
Preferably, the substrate tube for the graft of the present invention is made from a conventional ePTFE tube having a microstructure of nodes interconnected by fibrils and a mean fibril length or internodal distance of about 5-90 microns, preferably between about 10-45 microns and most preferably between about 10-30 microns or even 15-30 microns. Tubes of mean fibril length between about 10-30 microns are generally referred to hereinafter as 30 micron mean fibril length ePTFE tubes if a specific mean fibril length value is not otherwise provided. Tubes of this type are used as substrate tubes onto which is provided a luminal surface covering of another ePTFE material which provides the extremely smooth luminal surface. Preferably, this luminal ePTFE surface layer is in the form of an expanded PTFE film which may be oriented with the primary direction of film stretching (the predominant direction of orientation of the fibrils and the higher strength direction of the film) substantially parallel to the direction of blood flow over the luminal surface, or substantially perpendicular to that direction, or at any angle or angles between parallel and perpendicular. The film is preferably a film made as taught by U.S. Pat. No. 5,476,589 to Bacino, incorporated by reference herein. This film is referred to hereinafter as ""589 film.
These ""589 films typically have fibrils oriented in all directions within the plane of the film. This is the result of film expansion in both longitudinal and transverse directions. The fibrils in the longitudinal direction typically have a significantly larger mean diameter than fibrils oriented in other directions. This orientation of the larger diameter fibrils can be used to determine the longitudinal direction of the film, which corresponds with the direction of higher strength. The fibrils can be conveniently viewed with the aid of light microscopy.
In addition to providing the extremely smooth and non-adherent PTFE luminal surface, the ePTFE tube having the luminal surface covering of ePTFE film has good mechanical strength properties including good hoop strength and resistance to dilatation resulting from exposure to blood pressure over long periods of time, is readily sutured (typically having a density of about 0.5-0.7 g/cc) and has good suture retention properties. The presence of the luminal film layer augments the mechanical strength properties of the inventive graft. The combination of the 10-30 micron fibril length substrate tube and the smooth luminal surface of ePTFE film also provides good flexibility and handling properties to the inventive graft.
The good handling properties are generally the result of providing a graft with a density of less than about 1.55, more preferably less than about 1.5, 1.4, 1.3, 1.2, 1.0, 0.9, 0.8, 0.7, 0.6 and 0.5, with the lower densities generally offering the best handling (ease of bending without kinking and ease of suturing) and thus being the most preferred. Density is considered to be the mass divided by the gross volume of the graft material and thus includes any void volume resulting from any porosity of the graft material (i.e., bulk density expressed in grams per cm3). Because density is inversely proportional to porosity, it is a good indication of the amount of porosity or void space within the material. The density of non-porous PTFE is generally considered to be about 2.2 g/cc.
Density is to be determined for tubular vascular grafts by transversely cutting a representative 1 cm sample length of the graft with the result being a 1 cm long length of the graft tubing with ends cut perpendicular to the longitudinal axis of the graft tube. The tube is then cut through its wall thickness in the direction of its length (parallel to the longitudinal axis) and laid open with the result being a rectangular shape comprised of the graft material. The length and width are then measured along with the wall thickness to determine the bulk volume of the sample, after which the sample is precisely weighed to determine mass (weight). Wall thickness is measured by placing the sample between the pads of a Mitutoyo model no. 804-10 snap gauge having a part no. 7300 frame and gently easing the pads into contact with the opposing surfaces of the sample under the full force of the spring-driven snap gauge pads.
Grafts of the present invention as described above may have more than one component such as a first component of an ePTFE substrate tube and a second component of a layer of ePTFE film providing the luminal surface of the graft. The bulk density of such a graft thus includes the potentially different densities of the two or more components.
The vascular graft may be provided with any density within these described ranges in any combination with the previously described ranges of surface smoothness.
In an alternative embodiment the inventive graft may be made entirely from ePTFE film such as the ""589 ePTFE film; examples of methods of making film-tubes are described in WO 95/05555.
Various embodiments of the vascular graft of the present invention may be made to be quite thin, particularly when made as film-tubes. While they may be made as thin as a single layer of this film (about 0.004 mm), they are preferably of greater thicknesses such as 0.013 mm, 0.05 mm, 0.08 mm, 0.1 mm, 0.2 mm and 0.5 mm, in order to allow for practical handling. The thin embodiments find particular utility as intraluminal grafts and as stent coverings. Thinness is a.desirable attribute in terms of the wall of the graft encroaching minimally into the available luminal space.
The graft may optionally be provided with rapid recovery or xe2x80x9cstretchxe2x80x9d characteristics as taught by U.S. Pat. Nos. 4,877,661; 5,026,513 and 5,308,664. Rapid recovery may be provided to ePTFE in different amounts such as more than about 6%, 8%, 10%, 15%, 20%, 22%, 25%, 30% or 50%.
While the preferred method of making the inventive vascular graft involves providing an ePTFE substrate tube with a smooth luminal surface of ePTFE film, it is recognized that there may be other ways of making such a graft.